tbuckley/cabot-search huggingface dataset:
MEDB-76. Evaluating the B7-H3 checkpoint in Medulloblastoma
Authors: Kirsten Moziak, Elodie Picarda, Natalia Muñoz Perez, Phillip Galbo, Deyou Zheng, Xingxing Zang, Allison Martin
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: There is currently no curative therapy for recurrent/refractory MB. Novel approaches to MB include immunotherapy, such as targeting the immune checkpoint molecule B7-H3. B7-H3 is implicated in tumor metastasis and is highly expressed in MB. This study explores the effects of genetically knocking down B7-H3 in a murine model of recurrent/refractory medulloblastoma. METHODS: Murine MB cells were transduced with a CRISPR/Cas9 lentivirus to create a B7-H3 knockout. Knockout population was sorted twice via FACS by the AECOM flow cytometry CORE and confirmed by western blot and flow cytometry. Three healthy clones were used in subsequent studies, and compared to the wild type and the scramble control. IncuCyte live imaging technology was used to evaluate spheroid growth. Matrigel Boyden chambers were used to evaluate migration. Bulk RNA-seq was performed by the Yale University Core. RESULTS: B7-H3 knockout was successful in the murine MB model. Morphological differences were noted in the B7-H3 knockout cells. Spheroid formation assays show one of the clones with statistically slower growth kinetics compared to controls. Migration results are pending. RNA seq revealed similar clustering amongst knockouts, separate from controls with an enrichment in genes of morphologic development, WNT signaling and amoeboid migration. CONCLUSIONS: The morphologic changes in the B7-H3 knockouts suggest a potential growth differential. Although in vitro growth assays have shown mixed results regarding the effect of knocking out B7-H3 in spheroid formation, B7-H3 has been more directly implicated in migration and immune signaling. If migration is impaired, this will suggest that B7-H3 enhances malignant and metastatic potential in MB. Functional in vivo immune studies in syngeneic mice will investigate immune mediated effects of B7-H3 knockout in this tumor. If our studies support a role for B7-H3 in the development of MB, it may have important clinical implications, particularly for relapsed patients.
Novel platform for identifying multiple cancer-specific antigens.
Authors: Danielle Mor, Shakeel Farooqui, John Manavalan, Joseph Davis, Elliot Davis
Journal: Journal of Clinical Oncology (2022)

2530 Background: Virtually all cancer treatments that kill cancer cells also adversely affect normal cells and often have debilitating side effects. A key challenge has been to identify antigens that are suitable for antibody-based targeted therapeutics. We have developed a novel platform to detect and identify multiple cell surface antigens that are unique to human cancers. Methods: Breast Cancer cells (Hs578T) or Melanoma cells (Hs895.T) were injected into rabbits to generate polyclonal xeno-antibodies. The resulting serum against each cancer was then incubated with normal cells of the same tissue type derived from the same patients; Breast Epithelium (matched-pair Hs578Bst) or Skin Fibroblasts (matched-pair Hs895.Sk) in order to absorb antibodies that cross-react with antigens on normal tissue (U.S. Patent Application No. 16/243,161). Flow cytometry was used for measuring the binding capacity of the unfiltered serum and filtered serum (lacking cross-reacting antibodies) on both the cancer cells and normal cells. Cytotoxicity assays were performed using a secondary ADC (anti-rabbit IgG specific antibody conjugated to MMAF), to determine the cytotoxicity of the unfiltered antibodies and filtered antibodies on normal and cancer cells. Results: Flow cytometry revealed, for antibodies against breast cancer, there was 90.3% and 88.6% binding to breast cancer cells and normal breast epithelial cells, respectively, pre-filtration; and 78.9% and 23% binding, respectively, post-filtration. For antibodies against melanoma, there was 89.2% and 86.6% binding to melanoma cells and normal skin fibroblasts, respectively, pre-filtration; and 55.1% and 0% binding, respectively, post-filtration. The Table summarizes the cytotoxicity of unfiltered and filtered antibodies on cancer cells and normal cells. Remarkably, there was preferential killing of all the cancer cells tested by both unfiltered and filtered antibodies, while there was no cytotoxicity in the normal cells using filtered antibodies. Cytotoxicity was also observed when antibodies generated against one type of cancer were incubated with other cancer types. Conclusions: This data suggests that our xeno-antibody based method can detect cancer-specific sites, not found on normal cells, and diverse cancer types may share a common antigenic signature. These findings are significant for identifying unique antigens on cancer cells and designing targeted therapies against cancer. [Table: see text]
Preliminary RCC embolization before laparoscopic partial nephrectomy. Outcomes on surgical procedure
Authors: M. Maltagliati, L. Berti, D. Perri, U. Besana, C. Buizza, A.S. Gozen, M.C. Sighinolfi, B. Rocco, S. Micali, G. Bozzini
Journal: European Urology (2022)
Resource utilization and futile management in terminally ill cancer patients: A perspective from hospital-based palliative care program in Saudi Arabia.
Authors: Mohammed Saeed
Journal: Journal of Clinical Oncology (2022)

e24006 Background: The palliative care needs for cancer patients are on the rise across MENA region (Middle East and North Africa) with economical and quality of health-care implications. We believe this is the first reported study in the Saudi Arabia about resource utilization and futile management from a hospital-based palliative care program for terminally ill cancer patients. Methods: The data was collected retrospectively, the data collection took palace in the year 2018. The data collection tool consisted of seven parts, 1- Patient’s information, 2- Initial diagnostic procedures, 3- Imaging procedures 4- Pathology and laboratories workup, 5- Treatment modalities (if any), 6-Healthcare facility and resources utilization, 7- Palliative care utilization. Results: A total of 103 patients were included, their median age 66 years (20-94), and (58%) were females, the majority of the cases had stage IV cancer 99 (96.1%), half of them with gastrointestinal cancer 44 (42.7%). During their stay under PCU, 59 (57.3%) had chest X-rays, 21.4% ECG and 14.6% Abdominal ultrasound, various types of Computed Topographies (CT) were done for 18 patients (17.4%). Daily multiple times glucose checking was done for all patients, and complete blood count was done for 81.6%. Only 31 patients (30%) visited the Emergency Department ED after being transferred to PCU, 83 patients (80.6%) had no outpatient clinic visit at all. The median duration for palliative care was 17 days, while the median duration for oncology service is 193 days. The majority of the patients (n = 68) died within 30 days from transfer to palliative care, among them 4 patients (4 %) died on the same day of transfer. No statistically significant differences were found between males and females regarding the days from diagnosis to palliative transfer, days from diagnosis to palliative referral, the number of visits to ED, and the number of non- ICU admissions. Conclusions: Many patients were exposed to unnecessary procedures with no clinical implications, e.g. CT scans, EKGs, daily multiple labs. There is a significant delay in transferring the patients to palliative care service, policies and regulations are needed for timely transfer to palliative care services for cancer patients. Early complex advance care planning is an essential tool to combat futile management. 100% deaths in palliative care unit may reflect limitations for palliative care providers for alternate placements. Predominant use of palliative care unit for the end of life care would drive health care cost to higher level from direct and indirect expenses.
Single-cell RNA-seq analysis reveals BHLHE40-driven pro-tumour neutrophils with hyperactivated glycolysis in pancreatic tumour microenvironment
Authors: Liwen Wang, Yihao Liu, Yuting Dai, Xiaomei Tang, Tong Yin, Chaofu Wang, Ting Wang, Lei Dong, Minmin Shi, Jiejie Qin, Meilin Xue, Yizhi Cao, Jia Liu, Pengyi Liu, Jinyan Huang, Chenlei Wen, Jun Zhang, Zhiwei Xu, Fan Bai, Xiaxing Deng, Chenghong Peng, Hao Chen, Lingxi Jiang, Saijuan Chen, Baiyong Shen
Journal: Gut (2022)

Innate immunity plays important roles in pancreatic ductal adenocarcinoma (PDAC), as non-T-cell-enriched tumour. Neutrophils are major players in innate immune system. Here, we aimed to explore the heterogeneity and pro-tumour mechanisms of neutrophils in PDAC.We analysed single-cell transcriptomes of peripheral blood polymorphonuclear leucocytes (PMNs) and tumour-infiltrating immune cells from five patients with PDAC, and performed immunofluorescence/immunohistochemistry staining, multi-omics analysis and in vitro experiments to validate the discoveries of bioinformatics analysis.Exploration of the heterogeneity of tumour-associated neutrophils (TANs) revealed a terminally differentiated pro-tumour subpopulation (TAN-1) associated with poor prognosis, an inflammatory subpopulation (TAN-2), a population of transitional stage that have just migrated to tumour microenvironment (TAN-3) and a subpopulation preferentially expressing interferon-stimulated genes (TAN-4). Glycolysis signature was upregulated along neutrophil transition trajectory, and TAN-1 was featured with hyperactivated glycolytic activity. The glycolytic switch of TANs was validated by integrative multi-omics approach of transcriptomics, proteomics and metabolomics analysis. Activation of glycolytic activity by LDHA overexpression induced immunosuppression and pro-tumour functions in neutrophil-like differentiated HL-60 (dHL-60) cells. Mechanistic studies revealed BHLHE40, downstream to hypoxia and endoplasmic reticulum stress, was a key regulator in polarisation of neutrophils towards TAN-1 phenotype, and direct transcriptional regulation of BHLHE40 on TAN-1 marker genes was demonstrated by chromatin immunoprecipitation assay. Pro-tumour and immunosuppression functions were observed in dHL-60 cells overexpressing BHLHE40. Importantly, immunohistochemistry analysis of PDAC tissues revealed the unfavourable prognostic value of BHLHE40+ neutrophils.The dynamic properties of TANs revealed by this study will be helpful in advancing PDAC therapy targeting innate immunity.
Survival outcomes amongst patients with new onset diabetes preceding the diagnosis of pancreatic adenocarcinoma: Multicenter retrospective study.
Authors: Chirayu Mohindroo, Paul Stendahl Dy, Suraj Hande, Arun A. Mavanur, Ana De Jesus-Acosta, Florencia McAllister, Asha Thomas
Journal: Journal of Clinical Oncology (2022)

e16251 Background: In patients (pts) with new-onset diabetes (NOD) above the age of 50 years, 1% are diagnosed with pancreatic adenocarcinoma (PDAC) within three years. Based on this, NOD has been proposed as an important factor for early diagnosis of PDAC. Research has been directed towards investigating NOD vs Type 2 diabetes and association with PDAC. Limited data exists on its impact on the survival outcomes amongst PDAC pts. Methods: We retrospectively analyzed clinical data of 150 pts diagnosed with a pancreatic mass at three hospitals from 2014 to 2021. NOD group consisted of pts diagnosed with Diabetes or Pre-Diabetes defined as HBA1c &gt; 6.5% and 5.7-6.4%, respectively, within the three years prior to PDAC diagnosis. Primary aim of the study was the characterization of the impact of NOD on clinical outcomes. Results: 83 pts [mean age 68.32 yrs, 58% males, 61% white] were identified with biopsy proven PDAC, out of which, 9 (11%) pts had pre-existing Diabetes, 21 (25%) pts met the criteria for NOD group. In the NOD group whose weight was available (n = 15), 11 pts (79%) had experienced weight loss within one year of the NOD diagnosis with a median age of 68.46 yrs. No significant differences were noted between race (P = 0.36), age (P = 0.9), sex (P = 0.9), tumor location (P = 0.17), and chemotherapy received (P = 0.9) between the two groups. When comparing survival outcomes, no significant differences were noted in the metastatic cohort (n = 42, PFS HR 0.77, P = 0.4, OS HR 0.9 P = 0.7) including in the subgroup analysis for pts receiving FOLFIRINOX n = 20, PFS HR 0.59, P = 0.28, OS HR 0.66 P = 0.4) or Gemcitabine based treatment (n = 9, PFS HR 1.31, P = 0.7, OS HR 0.46 P = 0.3). In the resected cohort (n = 20), pts in the NOD group did worse than pts who did not meet the criteria with PFS 10 months vs. 18.3 months (P = 0.0058, HR 7.78), a similar trend was noticed in the OS 15.2 months vs. 28.2 months (P = 0.08 HR 2.98), but it did not reach statistical significance. Conclusions: Consistent with current literature, NOD preceding PDAC is distinct from Type 2 diabetes associated NOD, characterized by weight loss and occurring at a later age. Pts with NOD preceding PDAC were shown to have worse survival outcomes in the resected cohort. Larger studies need to be conducted in this context as this could have significant implications for PDAC screening and treatment.
MEDB-52. Organoids as preclinical models to improve and personalize disease outcome for sonic hedgehog medulloblastoma
Authors: Zelda Odé, Joris Maas, Mieke Roosen, Phylicia Stathi, Aniello Federico, Norman Mack, Benjamin Schwalm, Jens Bunt, Marcel Kool
Journal: Neuro-Oncology (2022)

Abstract Four main medulloblastoma (MB) molecular subgroups are known, including the sonic hedgehog (SHH) subgroup, which represents ~25% of MB cases. The 5-year overall survival of SHH-MB is ~80%. However, survival between patients is highly diverse and dependent on the driver mutation(s) of the tumor. Patients with TP53 mutated tumors (often accompanied with MYCN and/or GLI2 amplifications) don’t respond well to current therapies and have a 10-year overall survival below 20%. Therefore, there is a need for new and more tailored therapies for these patients. In this study we aim to screen patient-derived organoid models of TP53-mutated SHH MB with a library of ~200 different compounds. We have optimized the cultures of two PDX-derived and one patient-derived organoid line in vitro. The lines will be screened in a high-throughput manner and the best hits and combinations will be validated in corresponding in vivo PDX models. To further assess the role of specific mutations in therapy outcome of TP53-mutated SHH MB, cerebellar organoids generated from human iPSCs were genetically modified with overexpression of dominant-negative P53 (DNP53) alone or in combination with MYCN and/or GLI2. Introduction of DNP53 and MYCN overexpression in cerebellar organoids at day 28/35 leads to the outgrowth of a Ki67-positive proliferating mass after three weeks, indicating tumor growth. Further analyses are ongoing to see how they match SHH-MB patient tumors. These genetically engineered organoid models may elucidate the role of specific mutations in therapy response and/or resistance. In addition, as tumors in these genetically engineered cerebellar organoids arise in a microenvironment of normal cerebellar cell types, initial safety of drugs on cerebellar cells can be assessed. In conclusion, different organoid models of TP53-mutated SHH MB will enable us to find more effective treatments and to better understand how to treat patients with different mutation combinations.
Update from the PEDAL trial: A prospective single arm paired comparison of ability to diagnose and locate prostate cancer between multiparametric MRI and 18F-PSMA-PET/ CT
Authors: V. Tran, T. Sutherland, K. Taubman, S-F. Lee, D. Lenaghan, K. Sethi, N. Corcoran, N. Lawrentschuk, H. Woo, L. Tarlinton, T. Spelman, L. Thomas, R. Booth, J. Hegarty, E. Perry, L-M. Wong
Journal: European Urology (2022)
Beneficial impact of pork dry-cured ham consumption on blood pressure and cardiometabolic markers in individuals with high cardiovascular risk
Authors: S Montoro-Garcia, A Velasco-Soria, J Abellan-Aleman
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fundación Séneca de la Región de Murcia through the project “Jovenes Líderes en Investigación" RETOS-COLABORACIÓN (Ministerio de Ciencia y Tecnología. Background Evidence suggests that bioactive-peptides reduce hypertension and affect certain metabolic pathways. Methods Fifty-four volunteers with stage 1-hypertension and/or hypercholesterolemia and/or basal glucose &amp;gt;100 mg/dL were recruited and randomized to particular pork dry-cured ham (treatment) and cooked-ham (placebo) products for 2.5 months. Bioactive-peptides composition and enzyme inhibitory activities of both particular meat products were characterized. Treatment comparisons for the main effects were made using a 2 (treatment) × 2 (times) repeated measures minus the effect of cooked-ham. Results 24h mean systolic and diastolic pressures decreased up to 2.4 mmHg in the dry-cured ham period (p=0.0382 y p=0.0233, respectively) as well as the number of systolic pressure measures &amp;gt; 135 mmHg (p=0.0070). Total cholesterol levels also decreased significantly after dry-cured ham intake (p=0.049). No significant differences were observed between the two treatments for basal glucose, HOMA-IR index and insulin levels (p&amp;gt;0.05). However, significant rise of ghrelin level was observed, while leptin plasma values slightly decreased (treatment effect, p=0.0350 and p=0.0528, respectively). Conclusions This study suggested the beneficial effects of regular bioactive-peptides consumption on the improvement of systolic/diastolic blood pressures and emphasized the potentially regulation of ghrelin/leptin levels which provides new therapeutic opportunities for metabolic disorders in the cardiovascular primary prevention.
Mechanisms of acquired resistance to TRK inhibitors.
Authors: Guilherme Harada, Noura J. Choudhury, Alison M. Schram, Ezra Rosen, Yonina R. Murciano-Goroff, Christina J. Falcon, Clare Wilhelm, Lauren A. Kaplanis, Dazhi Liu, Jason C. Chang, Soo-Ryum Yang, Aradhika Dhawan, Patrick Evans, Casey Savin, Grace Grimaldi, Ronak H. Shah, Emiliano Cocco, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2022)

3104 Background: First-generation TRK tyrosine kinase inhibitors (TKIs) are approved in a tumor-agnostic fashion in more than 40 countries for patients with NTRK fusion-positive adult and pediatric cancers. While resistance to these agents has previously been described, the exact frequency with which major mechanisms of resistance emerges is not clearly understood. Methods: Patients with an NTRK-fusion-positive tumor who received a first-generation TRK TKI were eligible. We retrospectively identified those patients that had post-progression tumor tissue analyzed by next-generation sequencing (NGS). The pattern of serial resistance to a second-generation TKI was analyzed when available. Results: Eighteen patients were identified. The median age was 46 years (range 2-67). Nine unique fusions were detected in ten different tumor types. NTRK1, NTRK2, and NTRK3 fusions were found in eight (44%), one (6%), and nine (50%) patients, respectively. Thirteen patients (72%) were treated with larotrectinib and five patients (28%) received entrectinib. NGS (MSK-IMPACT n = 17, Foundation One n = 1) carried out on post-progression tissue revealed the following profile of acquired resistance: on-target resistance (83%, n = 15/18), off-target resistance (11%, n = 2/18), and no identifiable mechanism (6%, n = 1/18). Among patients with on-target resistance, the most common mutation involved the solvent front (87%, n = 13/15: n = 7 NTRK3 G623R, n = 4 NTRK1 G595R, n = 1 NTRK2 G639L, n = 1 NTRK3 G623E) followed by the gatekeeper region (13%, n = 2/15: n = 1 NTRK1 F589L, n = 1 NTRK3 F617I). Two patients developed off-target alterations. One acquired BRAF V600E mutation and the other MET amplification. Interestingly, solvent front mutation loss was observed in two patients who transitioned to and progressed on a second-generation TRK TKI. One patient with a baseline NTRK1 G595R mutation developed polyclonal resistance with acquisition of KRAS G12A and NTRK1 G667A alterations as well as NTRK1 G595R loss. The other patient with NTRK3 G623R developed an NTRK3 F617I gatekeeper mutation with NTRK3 G623R loss. Conclusions: In NTRK fusion-positive cancers, on-target resistance preferentially involving the solvent front is more frequent than off-target resistance to first-generation TKI therapy. Furthermore, the sequential use of second-generation therapy appears to alter the evolutionary kinetics of mutation retention and acquisition.
Targeting C3b/C4b and VEGF with a bispecific fusion protein optimized for neovascular age-related macular degeneration therapy
Authors: Shiqi Yang, Tong Li, Huixun Jia, Min Gao, Yiming Li, Xiaoling Wan, Zhen Huang, Min Li, Yuanqi Zhai, Xiaomeng Li, Xiaotong Yang, Tao Wang, Jian Liang, Qing Gu, Xueting Luo, Lei Qian, Shujie Lu, Junjian Liu, Yanping Song, Fenghua Wang, Xiaodong Sun, Dechao Yu
Journal: Science Translational Medicine (2022)

Antiangiogenesis therapies targeting vascular endothelial growth factor (VEGF) have revolutionized the treatment of neovascular ocular diseases, including neovascular age-related macular degeneration (nAMD). Compelling evidence has implicated the vital role of complement system dysregulation in AMD pathogenesis, implying it as a potential therapeutic strategy for geographic atrophy in dry AMD and to enhance the efficacy of anti-VEGF monotherapies in nAMD. This study reports the preclinical assessment and phase 1 clinical outcomes of a bispecific fusion protein, efdamrofusp alfa (code: IBI302), which is capable of neutralizing both VEGF isoforms and C3b/C4b. Efdamrofusp alfa showed superior efficacy over anti-VEGF monotherapy in a mouse laser-induced choroidal neovascularization (CNV) model after intravitreal delivery. Dual inhibition of VEGF and the complement activation was found to further inhibit macrophage infiltration and M2 macrophage polarization. Intravitreal efdamrofusp alfa demonstrated favorable safety profiles and exhibited antiangiogenetic efficacy in a nonhuman primate laser-induced CNV model. A phase 1 dose-escalating clinical trial (NCT03814291) was thus conducted on the basis of the preclinical data. Preliminary results showed that efdamrofusp alfa was well tolerated in patients with nAMD. These data suggest that efdamrofusp alfa might be effective for treating nAMD and possibly other complement-related ocular conditions.